: Retroviruses display a remarkable variety of interactions with their hosts, well beyond that known for any other virus group. This variety is a consequence of special features of the virus life cycle, including a high mutation rate during replication, the unique ability (and necessity to integrate their DNA at every replication cycle, and special features of certain parts of the genome, including the envelope gene and the LTR, that allow rapid adaptation to host cells displaying different surface receptors and in different transcription programs. For a number of years, our laboratory has been studying a number of different aspects of the evolutionary interaction of retroviruses with their host. These areas include: the mechanisms and role of genetic variation - point mutation, homologous and illegitimate recombination in genetic variation in vitro, the way in which LTR and env sequences are able to vary their patterns of expression and receptor usage; the nature and evolution of endogenous proviruses. Future studies will continue along the same lines. Our aims are: To study mutation and selection, we will continue development of our approach toward quantitation of very low-frequency; use these approaches to test models for retrovirus evolution (accumulation of point mutations and recombination) in simple culture; and develop and extend mathematical models for retrovirus variation and short-term evolution. To study evolution of env genes, we will analyze avian retrovirus env gene variants isolated by in vitro selection for extended host range; we will determine the evolutionary pathway by which such variants; we will determine the functional properties of "ancestral" env genes in endogenous; and we will test the possibility of evolution of env genes from normal cellular genes. We will study the evolution of endogenous proviruses by continuing to dissect the coevolution of endogenous MLV's and wild mice; using se sequences of endogenous human proviruses to test models of primate evolution; and testing why the large numbers of human endogenous proviruses do not give rise to infectious virus.